1. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 1
25 METABOLIC R ESPONSE
TO CRITICAL ILLNESS
Palmer Q. Bessey, M.D.
Metabolic Responses in Surgical Patients
Debility commonly accompanies surgical illness. It occurs in varying Features of Critical Illness
degrees after elective operations, major trauma, burns, infections, That Can Cause Debility
and other critical illnesses. Debility is caused by a variety of factors,
THE WOUND
including specific biochemical and physiologic alterations that usual-
ly occur in response to injury and disease, especially those that per- The surgical wound is
sist for a long time. Some aspects of surgical care that are common not only a site of tissue dis-
to almost all patients can also cause debility.This discussion will re- ruption but also a site of in-
view these clinical factors and metabolic responses in critically ill sur- flammation and repair [see
gical patients and will indicate how the clinician can manage them so 1:7 Acute Wound Care]. After resuscitation, the surgeon’s principal
as to minimize patient debility. task is to expedite and promote wound healing and restore tissue
The metabolic responses to critical illness have been studied in integrity. Because the wound is often the proximate cause of pa-
a variety of critically ill patients, especially those with trauma, burns, tient debility, providing optimal wound care amounts to providing
or sepsis.The responses are often grouped into phases on the basis the best patient care.
of their temporal relation to the injury or insult.The so-called ebb Wounds with necrotic or devitalized tissue (e.g., from ischemic
phase, which is the early phase of the injury response, is character- necrosis, gangrene, or burns), foreign debris, or grossly contaminat-
ized by (1) an elevated blood glucose level, (2) normal glucose pro- ed material do not heal readily, if they heal at all. Necrotic tissue and
duction, (3) elevated free fatty acid levels, (4) a low insulin concen- eschar (slough) must be debrided, usually surgically, although ap-
tration, (5) elevated levels of catecholamines and glucagon, (6) an plication of enzymatic agents to wounds has also been effective in
elevated blood lactate level, (7) depressed oxygen consumption, (8) some cases. Foreign material must be removed by either hydrother-
below-normal cardiac output, and (9) below-normal core tempera- apy or debridement. Pus must be drained or removed by irrigation
ture.1 The subsequent phase, the so-called flow phase, is character- and dressing changes. Contaminated wounds are left open so that
ized by (1) a normal or slightly elevated blood glucose level, (2) in- they can be repeatedly examined and further necrotic material can
creased glucose production, (3) normal or slightly elevated free fatty be removed. Open wounds should be covered with a dressing to
acid levels, with flux increased, (4) a normal or elevated insulin con- prevent drying (i.e., tissue oxidation) and further tissue slough, to
centration, (5) high normal or elevated levels of catecholamine and reduce bacterial contamination, and to prevent further mechanical
an elevated glucagon level, (6) a normal blood lactate level, (7) ele- injury. Unfortunately, none of the currently available dressing mate-
vated oxygen consumption, (8) increased cardiac output, and (9) el- rials achieve all of these goals. Once it becomes apparent that the
evated core temperature.1 wound tissues are viable and uninfected, the wound should be closed
The ebb phase is dominated by cardiovascular instability, altera- primarily if possible or with a skin graft.
tions in circulating blood volume, impairment of oxygen transport, The cellular processes involved in wound healing are critically de-
and heightened autonomic activity. Emergency support of cardio- pendent on adequate perfusion and delivery of oxygen, glucose, and
pulmonary performance is the paramount therapeutic concern. other essential nutrients. Inadequate perfusion may result in relative
Shock [see 8:3 Shock] is the prototypical clinical manifestation of the tissue ischemia and delay wound healing. A principal responsibility
ebb phase. After effective resuscitation has been accomplished and of the clinician is therefore to ensure adequate tissue perfusion dur-
restoration of satisfactory oxygen transport has been achieved, the ing the entire period of wound healing. For instance, resuscitation
flow phase comes into play. These responses are marked by hyperdy- from shock should be continued after blood pressure is stabilized
namic circulatory changes, signs of inflammation, glucose intoler- and until there is clinical evidence of adequate flow—usually associ-
ance, and muscle wasting. Surgical patients in the ICU usually ex- ated with warm extremities, pink nail beds, brisk capillary refilling,
hibit these clinical features; these patients and the clinical challenge full peripheral pulses, urine output greater than 0.5 ml/kg/hr (50 to
they pose are the focus of this chapter. 70 ml/hr in adults), clear sensorium, and improving metabolic acido-
When wounds are closed and infection has resolved, repletion of sis. Adequate oxygenation must also be ensured. Occasionally, inva-
lean tissue and fat stores and restoration of strength and stamina sive monitoring of cardiopulmonary performance [see 8:4 Cardio-
can begin.This final, anabolic phase often begins near the time of vascular Monitoring] and tissue oxygenation as well as phar-
hospital discharge and may persist for months before the patient macologic support may be required to ensure adequate perfusion
fully recovers. and oxygen delivery.

2. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 2
Patient problems that lead to debility
Wound Pain Inflammation
Debride necrotic tissue and foreign debris. Use systemic analgesics judiciously. Fever
Drain pus. Consider patient-controlled analgesia. • If < 38.5° C (101.3° F), usually no
Avoid drying of tissues. Consider regional (epidural) anesthesia. treatment or evaluation is necessary.
Maintain satisfactory cardiopulmonary • If ≥ 38.5° C (101.3° F), survey for
performance to optimize oxygen delivery. source of infection; consider
Expedite wound closure. administering antipyretics.
For clean surgical wounds: • If > 41° C (105.8° F), increase
• Handle tissues gently. antipyretics; consider use of cooling
• Use precise surgical technique and blankets, ice packs, etc.
hemostasis. Altered thermoregulation
Avoid contamination. • Maintain warm environment
Use primary closure when possible. (26°–33° C [78.8°–91.4° F])
to achieve thermal comfort.
Anorexia
• Limit period of fasting to 3–4 days.
Immunosuppression
• Sterile technique for all procedures,
including intravenous line
manipulations, suctioning, etc.
• Universal precautions; change gloves,
wash hands between patients.
Metabolic response to critical illness
Hyperdynamic or hypermetabolic state Muscle wasting Glucose intolerance
Expect Expect Expect
• Tachycardia • Rapid wasting of muscle and loss of • Hyperglycemia that is aggravated by
• Widened pulse pressure strength and endurance glucose intake, infection, and other
• Increased cardiac output • Increased osmotic load filtered by stressors
• Increased O2 consumption kidney • Relative insensitivity to insulin, which
• Increased minute ventilation • Increased formation and urinary improves with recovery
• Increased energy expenditure loss of urea Provide
• Fever • Increased urinary loss of potassium, • Glucose control
• Sodium and water retention phosphorus, and magnesium • Human insulin I.V. to maintain
Provide Provide blood glucose in a target range of
• Volume and pharmacologic support of • Increased protein or amino acid intake 110–160 mg/dl
cardiovascular performance as to 15%–20% of total energy • Maintenance nutritional support
appropriate • Increased intake of potassium, • Glucose as 60%–75% of total energy
• Warm environment (26°–33° C) phosphorus, and magnesium (5–7 mg/kg/min or 7–10 g/kg/day)
• Increased water intake • Massage, active and passive exercise, • Lipid as 25%–40% of total energy
• Increased caloric intake and early mobilization
• Judicious sedation and analgesia

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8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 3
Infection Hospital treatment
Initially diagnose by abrupt changes in fever, Bed rest:
leukocytosis, hyperglycemia, pulmonary • Encourage frequent turning, coughing, and
function, or pulse and blood pressure. deep breathing.
Culture appropriately to establish micro- • Encourage active, assisted exercise in bed
biologic diagnosis. when feasible.
Administer broad-spectrum antibiotics • Move to chair as soon as possible.
empirically to cover likely pathogens if signs of • Use incentive spirometer or similar device.
organ system dysfunction and of sepsis develop. • Practice good hygiene and skin care, and
Debride necrotic tissue. provide massage.
Establish drainage; remove catheters. Food deprivation:
Prevent contamination of different sites on • Limit period of fasting to 3–4 days.
same patient. • Begin nutritional support as soon as needed.
Prevent cross-contamination between patients. • Provide enteral feeding when possible.
Invasive devices:
• Remove as soon as no longer required.
• Remove I.V. lines placed under suboptimal
conditions as soon as feasible.
• Consider changing I.V. lines or rotating site
every 2 or 4 days.
• Change I.V. site if redness or inflammation
develops.
Sleep deprivation:
• Reduce lighting and noise in ICU
periodically, especially at night.
• Orient patient frequently to time of day and
situation.
• Use sedation judiciously.
Metabolic Responses in Surgical Patients

4. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 4
Contused tissue, fractures, tissues surrounding an abscess or site on pulmonary function in patients with rib fractures or truncal
of infection, inflammatory sites such as the pancreas in pancreatitis wounds.4 This technique requires placement of a catheter in the epi-
or the lung in acute respiratory distress syndrome (ARDS)—in fact, dural space.
any mass of inflammatory tissue—can be considered to constitute Patients must be monitored closely, and the dosage schedule must
the patient’s wound because resolution of those focal sites of inflam- be individualized.This technique is best suited to patients who will
mation depends on the same basic cellular processes as does healing be relatively inactive for 24 to 36 hours postoperatively and who can
of an external wound. be observed closely, such as patients in the ICU.
Patients with a large total mass of inflammatory tissue—large
INFLAMMATION
wounds—usually are critically ill and clearly manifest most of the
metabolic responses associated with critical illness [see Metabolic Re- Elevation of body temper-
sponses That Can Cause Debility, below]. In contrast, patients with ature above normal, leuko-
small wounds do not appear critically ill and are not significantly de- cytosis, and other signs of
bilitated. Although elective operations result in wounds, the incisions inflammation are common
are made under sterile, controlled conditions; there is minimal direct features of critical surgical
tissue injury, little contamination, no shock, and limited net loss of illness and should be expect-
blood and fluid.The incisions are closed primarily and most often ed. The extent of tempera-
heal expeditiously.With the current proliferation of minimally inva- ture elevation is generally
sive surgical techniques, operative incisions are now even more limit- proportional to the severity of illness. In a patient with a major
ed, patients recover more rapidly, and the resultant debility is burn—an extreme example of critical surgical illness—body temper-
minimal—often little more than a transient indisposition. ature may be as high as 39° C (102.2° F). The leukocyte count is
also typically elevated and may be as high as 20,000 cells/ mm3 dur-
PAIN
ing satisfactory recovery. A normal or subnormal body temperature
Virtually all surgical pa- or white blood cell count is atypical and may indicate sepsis, drug-in-
tients experience some pain. duced leukopenia, or limited physiologic reserve. For example, a crit-
Pain usually occurs in asso- ically ill elderly patient with a major injury or infection may be
ciation with an incision or afebrile and have a white blood cell count in the normal range.
with a wound resulting from Fever, however, is also a cardinal sign of infection. It may be diffi-
fracture, burn, contusion, or cult to distinguish between a typical postoperative or posttraumatic
another type of injury. In ad- fever and a fever caused by invasive infection. An acute elevation in
dition to creating an unpleasant subjective experience, pain often rectal temperature of 1.0° to 1.5° C (1.8° to 2.7° F) that occurs
limits physical activities, such as turning in bed, deep breathing, within a short period or a rectal temperature higher than 38.5° C
coughing, and walking, and thereby directly interferes with recovery. (101.3° F) should be considered indicative of infection and should
A variety of techniques are available for pain management. However, be investigated thoroughly. Sputum, urine, and blood cultures
each approach has side effects, the potential for abuse, or other fea- should be obtained, and all wounds should be inspected carefully
tures that limit its application. for signs of inflammation or infection. Devices commonly associat-
Acute pain has traditionally been managed by intermittent par- ed with nosocomial infection—intravenous cannulas, urinary cath-
enteral administration of narcotic analgesics when requested by the eters, and endotracheal tubes—should be removed as soon as feasi-
patient or when the nurse perceives the patient to be in pain.The in- ble or else changed (see below).
travenous route is now preferred, because it does not require a painful Because inflammation is such a prominent feature of all critical ill-
injection and avoids potential uptake abnormalities. Intravenous anal- ness, including that in patients with serious infectious complications
gesics have a short duration of action and must be given frequently to of chronic diseases, several clinical syndromes have been defined in
maintain good, sustained pain control; the dose also must be relative- an effort to stratify patients according to the severity of their inflam-
ly small to minimize the side effects of sedation and impaired gastric matory responses [see Table 1].5 These syndromes are associated with
motility.Thus, this approach to pain control is relatively labor inten- increased mortality, even in the absence of documented infection.6
sive.Theoretically, this approach can prevent overuse of narcotics; in In the remainder of this chapter, I will refer repeatedly to the meta-
practice, it often results in inconsistent pain control and underdosing. bolic responses to critical illness; this term incorporates these inflam-
Continuous infusion of narcotic analgesics provides more consis- matory syndromes and more besides, and its use permits a more
tent pain control and is common in the ICU. The dose should be ad- comprehensive discussion.
justed upward before painful procedures but otherwise should be Mild elevation of body temperature is usually well tolerated and re-
kept as low as possible to avoid ileus and prolonged sedation. Patient- quires no specific treatment. However, a higher fever may impose sig-
controlled analgesia (PCA) is an extension of this approach. The pa- nificant stress on the patient, as indicated by pronounced tachycardia,
tient controls a pump that administers a prescribed dose of the agent tachypnea, malaise, and, occasionally, restlessness.Thus, a body tem-
when activated; the clinician determines the amount of drug in each perature higher than 39° C (102.2° F) is usually treated with an-
dose and the total dose permissible in a given period.This technique tipyretics (e.g., acetaminophen, aspirin, indomethacin, or ibuprofen).
has been well accepted by patients who are awake and alert and are The fever experienced by critically ill patients is an upward adjust-
capable of controlling the system. One benefit is that the total amount ment of the thermoregulatory center in the brain, the central ther-
of drug administered for pain relief is usually less than is given in a mostat. A consequence of this adjustment is that the patient usually
conventional as-needed dosing schedule.2 prefers a warmer environmental temperature than do normal indi-
Administration of local anesthetics or narcotics into the epidural viduals. An ambient temperature in the hospital that is comfortable
space may provide effective local pain relief without the sedating ef- for the staff is often perceived as cool by the patient, who must gen-
fects of parenteral narcotics. In addition, epidural anesthetics (but erate extra heat to maintain the adjusted body temperature. Thus,
not opioids) reduce postoperative ileus.3 Effective epidural analgesia patient areas of the hospital should be kept warm, usually in the
can be maintained for several days and may have a beneficial effect range of 26° to 33° C (78.8° to 91.4° F).This temperature range will

5. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 5
ment of oxygenation, and other signs associated with the septic re-
Table 1—Components of sponse. The challenge for the clinician is to distinguish patients in
Inflammatory Syndromes5 whom this response is caused by established infection from those in
whom it is not the result of an infectious focus. A temperature higher
Systemic inflammatory response syndrome (SIRS)—two or more of than 38.5° C (101.3° F) or an acute increase in temperature accom-
the following are required: panied by an abrupt change in the white blood cell count should
Temperature > 38° C (100.4° F) or < 36° C (96.8° F)
prompt investigation for a developing infection [see Figure 1], which
Heart rate > 90 beats/min
would include appropriate cultures and other diagnostic studies.
Respirations > 20/min
WBC > 12,000/mm3, < 4,000 mm3, or > 10% bands
Other signs that suggest underlying infection include relative hy-
pothermia, leukopenia, thrombocytopenia, abrupt elevation or de-
Sepsis
pression of the blood glucose level, restlessness, lassitude, hyperpnea,
SIRS
and failure to progress as expected.
Clinically likely source of infection (does not require bacteriologic
confirmation) If the presence of infection is suggested by the clinical setting, the
magnitude of fever, or any other systemic signs (such as renal or respi-
Severe sepsis
Sepsis
ratory dysfunction, marked hyperglycemia or hypoglycemia, hypo-
Impaired cardiovascular performance necessitating fluid resuscitation thermia, or hypotension), broad-spectrum antibiotic coverage should
be instituted empirically before culture results are available [see 8:14
Septic shock
Clinical and Laboratory Diagnosis of Infection]. Specific antimicrobial
Severe sepsis
Impaired cardiovascular performance necessitating inotropic support
therapy should be begun once the presence of infection has been con-
firmed and the microbiologic diagnosis has been established. Other
therapeutic measures may also be necessary to treat the infection.
Draining an abscess, debriding or excising necrotic tissue, removing
promote patient comfort and reduce the physiologic demands of indwelling catheters and placing new ones at other sites, performing
cold stress.When moved into the OR, radiology suite, or other typi- therapeutic bronchoscopy to ensure drainage of major airways, or cre-
cally cool environments, patients should be insulated, or the room ating a tracheostomy in the patient who requires an airway for im-
should be warmed. proved bedside pulmonary toilet may also be advisable.
Attempts to treat a patient with fever by surface cooling (ice packs, Because all critically ill patients are at risk for infection, efforts di-
alcohol rubs, cooling blankets) are not uncommon. Rather than ad- rected at prevention are worthwhile. Medical and nursing personnel
dressing the altered physiology underlying the fever, however, surface can prevent the transmission of organisms from one patient to an-
cooling imposes a marked cold stress on an already critically ill and other by effective hand washing between patient contacts. Gloves
stressed patient. Except in the presence of hyperpyrexia (tempera- used by health care workers for their own protection whenever they
ture ≥ 41° C [105.8° F]), surface cooling should be avoided; an- have contact with patients must be changed between patients. Of
tipyretics should be administered first to reduce body temperature. course, sterile techniques should be used during invasive procedures.
During acute surgical illness, patients typically have a poor ap-
petite. Even when able to eat, they often do not consume sufficient
nutrients even to approximate their needs. Accordingly, the clinician Phagocytic Activity
should initiate exogenous nutritional support early in the patient’s
Depression of Plasma Amino Acids, Iron, and Zinc
course, especially if it is likely to be prolonged by the need for addi-
tional reparative procedures, such as fracture fixation or delayed Saluresis; Retention of Urinary Phosphate and Zinc
Increased Secretion of Glucocorticoids and Growth Hormone
wound closure. Increased Deiodination of Thyroxine
Some degree of immunosuppression is also a common feature of Increased Synthesis of Hepatic Enzymes
inflammation.Thus, critically ill patients are more susceptible than
Secretion of Acute-Phase Serum Proteins
normal to colonization and infection with a variety of microorgan- Carbohydrate Intolerance
isms. Special attention to sterile technique during bedside proce- Increased Dependence on Lipids for Fuel
dures, the use of universal precautions, and hand washing after each
Increased Secretion of Aldosterone and
patient encounter by all care providers should help reduce the risk of Antidiuretic Hormone
nosocomial infection. + 2+
Negative Balances Begin (N, K , Mg ,
3– 2+ 2–
INFECTION PO4 , Zn , and SO4 )
Retention of Body Salt and Water
Infections in hospitalized
patients fall into two categor- Increased Secretion of Thyroxine
ies: they may be directly re- Diuresis
lated to the patient’s primary
Return to Positive
disease or injury (e.g., inva- Balances
FEVER
sive burn wound sepsis, gan-
grene of an ischemic limb, or
intra-abdominal abscess after perforated diverticulosis), or they may INCUBATION ILLNESS CONVALESCENT
develop as a complication of physiologic support (e.g., pneumonia PERIOD PERIOD
after prolonged mechanical ventilatory support).
MOMENT
Early diagnosis and treatment of infection in surgical patients can
OF EXPOSURE
minimize debility. Most critically ill surgical patients experience fe-
ver, leukocytosis, tachycardia, widened pulse pressure (reduced vas- Figure 1 Illustrated is the time course of events that constitute the
cular resistance), glucose intolerance, fluid retention, some impair- classic response to bacterial infection.253

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8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 6
Sites of insertion of intravascular cannulas should be inspected regu- technique. Such lines should also be changed if the puncture site is
larly, and the catheters should be moved to a new site if the skin be- red, inflamed, or purulent.With most of these devices, the risk of in-
comes reddened or if pus is observed. Antibiotic-impregnated cen- fectious complications increases after 3 or 4 days.11 Regular replace-
tral venous catheters may reduce the incidence of catheter-related ment is commonly practiced, especially if the patient becomes feb-
infection and thereby lower the frequency with which lines must be rile. Catheters impregnated with antibiotics appear not to require
replaced.7 The prophylactic use of antibiotics in the ICU is contro- such frequent exchanges and may be safely used for longer periods.7
versial8-10 and cannot be encouraged at present.
Sleep Deprivation
IATROGENIC FACTORS
Normal sleep patterns are disturbed in ICU patients, in part be-
cause of the constant light and noise in the ICU and because of
Bed Rest repetitive stimulation by the ICU staff. Such disturbances, in combi-
Bed rest and inactivity nation with other stresses associated with illness, often result in con-
both contribute to loss of fusion, disorientation, anxiety, and, occasionally, frank psychosis. As
muscle mass and strength. many efforts as possible should be made to orient the patient, includ-
Immobility may result in ing the use of wall calendars, clocks, and other methods that serve as
progressive atelectasis, respi- normal day-night indicators (e.g., turning the lights down at night).
ratory insufficiency, and pulmonary sepsis. If immobility is pro- Even the personal activities of daily living, such as bathing and shav-
longed, open pressure sores may develop over bony prominences. ing, can serve as time cues. Patients should be reassured and remind-
Thus, patients should be turned frequently, and their position should ed about the date, the time, their location, and the reason for their
be changed often. Patients who are able to participate actively in repo- hospitalization. Sedatives and hypnotics may be useful in critically ill
sitioning themselves should be encouraged to do so by helping to patients but occasionally have a paradoxically excitatory effect.
turn or lift themselves. They should be urged to take deep breaths
and cough. An incentive spirometer is inexpensive and is often help-
ful in this regard. When patients are hemodynamically stable, they Metabolic Responses That
should be moved to a chair, provided that no musculoskeletal con- Can Cause Debility
traindications are present. This position improves ventilation and All of the clinical factors
helps preserve postural reflexes. Patients should assist in sitting up as of surgical care contribute to
much as is feasible. Even simple actions such as standing in place or or affect various physiologic
bearing weight during the transfer may be beneficial. Active and pas- and biochemical alterations
sive range-of-motion exercises can help maintain joint function. that occur in response to crit-
Proper positioning of the extremities may be necessary to prevent ical illness; these physiologic
contractures and to preserve range of motion. and biochemical alterations collectively constitute the metabolic re-
Skin integrity is preserved not only by frequent position changes sponse to critical illness.The intensity and duration of this response de-
but also by attention to hygiene. Patients should be bathed regularly, termine debility. Current critical care management generally supports
with special attention paid to intertriginous areas. Any soilage with rather than modifies the response.Three major features of the meta-
blood, stool, urine, or other material should be removed and the skin bolic response to critical illness affect clinical care: the hyperdynamic
thoroughly dried. Massage and application of moisturizing lotions or hypermetabolic state, muscle wasting, and glucose intolerance.
are also helpful.The use of foam or air mattress pads that distribute
HYPERDYNAMIC OR HYPERMETABOLIC STATE
body weight over a large area or low-air-loss beds may also benefit
the patient confined to bed for a prolonged period. However, these In recovery from critical illness, several organ systems function
devices are no substitute for good nursing care. at an accelerated pace. Principal among these is the cardiovascular
system. Tachycardia and a widened pulse pressure are typically
Food Deprivation present and reflect cardiac output greater than that expected in a
Food is commonly withheld from the patient before and during resting, healthy individual.The increased blood flow is distributed
various diagnostic and therapeutic procedures as well as before oper- to most vascular beds, especially to inflammatory tissue or the
ations or after injury. Starvation for several days appears to be well wound, and supports increased cellular activity in the healing
tolerated by patients who were relatively well nourished before their wound. In the kidneys, increased flow is associated with an elevat-
critical illness. However, if food deprivation is prolonged, the compli- ed glomerular filtration rate.Thus, drug excretion may be acceler-
cations of starvation will compound the effects of critical surgical ill- ated, and increased dosages may be required to maintain therapeu-
ness.Total starvation should usually be limited to a period no longer tic plasma concentrations.
than 3 or 4 days. Nutritional support should be instituted via the Accompanying the increases in cardiac output and regional blood
most effective and safest route possible [see 8:22 Nutritional Support]. flow is an increase in oxygen delivery (transport) to the microcircula-
tion.This increase in oxygen delivery supports the enhanced oxygen
Invasive Devices requirements of several organ systems.Total body oxygen consump-
A variety of tubes, catheters, and drains are essential for the prop- ˙
tion (VO2) is greater than normal because of the increased oxidation
er care and monitoring of critically ill patients. However, each of of body fuels—carbohydrates, fats, and amino acids—needed to pro-
these devices transgresses a normal barrier to infection, and each is vide the energy to drive the cellular machinery at this accelerated
associated with infectious risks and other complications. An invasive pace [see Figure 2].These reactions produce heat. Heat production,
device should be removed as soon as it is no longer required. Intra- also referred to as energy expenditure or metabolic rate, is increased
venous lines placed in the emergency room or under less than ideal in critically ill patients, who thus are said to be hypermetabolic.
conditions (e.g., at the scene of an accident or while the patient is en ˙
The increase in VO2 is paralleled by increased carbon dioxide pro-
route to the hospital) should be removed as soon as possible and re- ˙
duction ( VCO2), which, under normal conditions, stimulates breath-
placed, if necessary, with new devices by means of appropriate sterile ing and augments minute ventilation. For patients who require ven-

7. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 7
tilatory assistance, the ventilator should be set to deliver a minute 180
ventilation that is greater than normal.
As discussed earlier, critically ill patients typically have a fever and
prefer warmer ambient temperatures than normal individuals. In 160
these patients, metabolic rates increase in part to maintain a higher
Resting Metabolic Rate (%)
than normal core temperature. A warm environment may help blunt
the patient’s increased heat production and energy needs. 140
Associated with the hyperdynamic state of critical illness is expan-
sion of the extracellular fluid (ECF) compartment.Total body water
and total body sodium are increased.This expansion occurs periop- 120
eratively or with resuscitation after injury. Short-term changes in
body weight reflect alterations in body water and in lean tissue mass.
100
Slow, persistent expansion of the ECF may mask loss of tissue mass.
Conversely, spontaneous diuresis of sodium and water during recov-
ery may lead to pronounced weight loss in a patient who otherwise Normal Range
80
appears to be progressing well.
During critical illness, the daily loss of body water is increased in
several ways. Fever accelerates insensible loss of body water, and re-
60
nal loss may be greater than normal because of the increased os- 0 10 20 30 40 50 60 70
motic load caused by the breakdown of lean tissue (see below). If Time (days)
there are open wounds, evaporative water loss is markedly increased,
in proportion to the size of the open wound. Thus, maintenance 50
water requirements may be greater than normal. It is often neces-
sary to monitor both the intravascular fluid volume, using values for
central venous or pulmonary arterial wedge pressures, and the ECF 40
composition or tonicity, as indicated by changes in serum sodium
Nitrogen Excretion (%)
concentrations.
The clinician should provide not only volume and possible phar- 30
macologic support to maintain a hyperdynamic circulation but also
an increased amount of calories to meet the patient’s elevated energy
needs.These needs can often be reliably estimated on the basis of the 20
patient’s age, sex, body size, and critical illness. Occasionally, it may
˙ ˙
be helpful to measure the patient’s VO2 and VCO2 and to use these
values to calculate daily caloric requirements. 10
In addition to providing cardiopulmonary and nutritional support
to critically ill, hyperdynamic patients, the clinician should try to Normal Range
neutralize factors that may augment the hyperdynamic response to 0
0 6 12 18 24 30 36 42
critical illness. Judicious analgesia and sedation provide metabolic Time (days)
benefits and relieve pain and anxiety. Providing a warm environment
mitigates the hyperdynamic response by reducing cold stress. An- Severe Moderate Mild
tipyretics reduce the heart rate during periods of extreme fever. Illness Illness Illness
MUSCLE WASTING Figure 2 Increased resting metabolic activity (hypermetabolism)
and increased nitrogen loss are closely related during critical surgical
The distinguishing feature illness. Both correlate with the severity of illness and return to nor-
of the debility of critical ill- mal as the patient recovers. Patients with severe illness are repre-
ness is marked muscle wast- sented by the solid red line, those with moderate illness by the broken
ing and weakness. Wasting red line, and those with mild illness by the solid black line; the nor-
is in part a consequence of mal range is shown by the light-red bar.
accelerated muscle protein
breakdown, which is gener- 20% to 25% of total calories as protein or amino acids. BUN may be
ally related to the severity of illness [see Figure 2].The increased pro- higher than normal (at least 20 to 30 mg/dl) with this level of amino
tein breakdown presumably serves to mobilize amino acids for syn- acid intake, even if renal function is normal.
thesis of new protein in wounds; for proliferation of phagocytes, In addition to amino acids, other intracellular constituents are re-
macrophages, and other cellular components involved in wound leased by these catabolic processes and subsequently excreted.Thus,
healing; and for synthesis of acute-phase proteins and glucose in the metabolic alkalosis often develops, associated with mild hypochlore-
liver.The increased synthetic work and processing of amino acids in mia and with reduction in total body potassium and magnesium. Re-
the liver result in increased production of urea, which is filtered and pletion with potassium chloride and magnesium sulfate is usually ef-
excreted by the kidneys. In the presence of renal dysfunction, blood fective. During nutritional support, generous amounts of potassium
urea nitrogen (BUN) may rise rapidly. (≥ 100 mEq/day), magnesium (≥ 30 mEq/day), phosphate (20 to 30
To reduce muscle wasting, additional exogenous protein or amino mmol/day), and trace minerals should be provided to promote syn-
acids are provided through nutritional support. In general, protein thesis and restoration of intracellular proteins and other constituents.
needs increase in proportion to caloric requirements. However, for Muscle mass is also lost as a result of disuse.The critically ill patient
the critically ill surgical patient, it may be beneficial to provide at least is usually confined to bed and may be further immobilized because of

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8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 8
Table 2—Blood Glucose and Insulin Concentrations in Burn Patients1
Fasting Blood Glucose
Burn Size Postburn Day
Group N Basal Insulin (µU/ml)
(% TBS) Studied (mmol/L) (mg/dl)
Control subjects 12 — — 3.88 ± 0.11 69.8 ± 1.9 22 ± 3
Resuscitated burn patients 4 71 1 7.77 ± 0.61 139.9 ± 10.9 20 ± 6
Hypermetabolic burn patients 17 42 9 6.27 ± 0.28 112.9 ± 5.0 22 ± 2
Convalescing burn patients 5 56.5 69 4.05 ± 0.33 72.9 ± 5.9 14 ± 1
Septic burn patients 15 71 10 6.43 ± 0.55 115.8 ± 9.9 22 ± 4
Treated septic burn patients 4 72 11 6.11 ± 0.83 110.0 ± 15.9 12 ± 3
traction, monitoring devices, mechanical ventilation, and sedation. subcutaneous uptake caused by variations in blood flow. Because of
Massage, passive range-of-motion exercises, early mobilization, and its short half-life, intravenous insulin must be administered either in
limited bed exercises (e.g., moving from bed to chair, use of a trapeze frequent intermittent doses or by continuous infusion. Both tech-
bar to assist with positioning) may be helpful in reducing muscle niques can be used with a reasonable margin of safety. Blood glucose
wasting and debility. levels may be determined rapidly by using a portable glucose analyz-
er at the bedside on a small blood sample drawn every 1 or 2 hours.
GLUCOSE INTOLERANCE
On the basis of the blood glucose value, a predetermined insulin
Critically ill patients usu- dose may be administered (on a so-called sliding scale) or the infu-
ally exhibit glucose intoler- sion rate may be adjusted. Current data suggest that the optimal
ance similar to that seen in range for blood glucose values in critically ill surgical patients is 80 to
diabetic patients [see Table 2]. 110 mg/dl (4.4 to 6.1 mmol/L).12 One half to two thirds of the total
Hyperglycemia during criti- insulin dose required to maintain blood glucose in this target range
cal illness is a result of both in a 24-hour period may be added to the intravenous feeding regi-
increased production of glu- men on the next day. In this way, the blood glucose level is ultimate-
cose by the liver and decreased uptake of glucose by insulin-depen- ly maintained in an acceptable range.
dent tissues. These processes occur despite normal or exaggerated The degree of glucose intolerance will vary over the course of the
insulin responses to hyperglycemia. critical illness.Therefore, regular monitoring of blood glucose concen-
Hyperglycemia may be marked, especially if the patient is receiv- trations is advisable, even after adequate control has been achieved.
ing a large glucose load, such as might be provided with nutritional Further episodes of stress-inducing conditions, especially infection,
support. Hyperglycemia may exacerbate ventilatory insufficiency, may exacerbate glucose intolerance; an abrupt rise in blood glucose
contribute to hepatic dysfunction, and provoke osmotic diuresis, concentration may be the first indication of impending sepsis. As the
thereby leading to dehydration and a hyperosmolar state. Hyper- patient recovers, glucose tolerance improves and the requirement for
glycemia has also been associated with an increased risk of postoper- insulin decreases.When the patient is transferred from intravenous
ative infection, renal failure, increased transfusion requirements, and nutrition to enteral nutrition, insulin requirements often decrease
death in critically ill patients.Vigorous attempts to control the blood despite similar nutrient intake.
glucose concentration are therefore warranted. Glucose remains an important fuel during critical illness, especial-
The provision of safe amounts of glucose and the administration ly for healing wounds. However, the ability to utilize glucose effec-
of exogenous recombinant human insulin are the mainstays of ther- tively appears to be reduced. Most of the total energy administered
apy for glucose control. Because insulin resistance is present in pa- in nutritional support should be provided by glucose (60% to 75%
tients with critical illness, relatively large quantities of insulin may be of total calories).The dose of glucose should, however, be limited if
required to control the blood glucose level. Intravenous administra- marked hyperglycemia cannot be readily controlled with insulin.The
tion of insulin provides rapid control and prevents unpredictable remaining calories can be provided by fat emulsion.
Discussion
The clinical features of all critical illnesses are similar, regardless of immunologic abnormalities that may make them more susceptible
the type of insult sustained, be it injury, operation, or infection. Sim- to invasive infection by a variety of microorganisms, including those
ilar responses can be seen in a wide variety of animals that have been that are not usually pathogenic.The syndrome of multiorgan fail-
injured or challenged by invasive infection.13,14 These responses to ure and sepsis that may develop in association with the metabolic
critical illness presumably evolved because they confer an advantage responses to critical illness is often the final route to death [see 8:13
with respect to survival. In fact, it seems indisputable that when an Multiple Organ Dysfunction Syndrome].Thus, in some ways, certain
individual organism acquires an enhanced ability to recover from an metabolic responses seem maladaptive in that they retard recovery
injury or infection, the species is thereby benefited. Accordingly, the and lead to organ failure and death.
metabolic responses to critical illness are often considered to be adap- An improved understanding of the metabolic responses to critical
tive reactions that serve to promote recovery. illness may benefit patients in two ways. First, it may facilitate the de-
There is a cost for this benefit, however, and that is debility. In velopment of improved supportive therapies. Much of current criti-
addition, the metabolic responses to critical illness can lead to or- cal care practice is based on our understanding of these processes
gan system dysfunction. Critically ill patients also typically have and has been designed to support them. Second, a better under-

9. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 9
standing of the mechanisms underlying the metabolic responses to cle is resistant to insulin after injury or critical illness, and its capacity
critical illness may lead to strategies for altering the responses so as to for glucose storage is reduced significantly.This response contributes
stimulate those features that are beneficial and promote recovery and to glucose intolerance and helps direct glucose to the healing wound.
to suppress or limit those features that are debilitating or lead to or- The gut was long considered to be essentially inactive during con-
gan system dysfunction. valescence, but it now appears to play a central role in the metabolic
response to critical illness [see 8:22 Nutritional Support]. During crit-
ical illness, the gut utilizes glutamine as its principal fuel, converting
Integrated Metabolic Response to Critical Illness glutamine to alanine, which is transported to the liver by the portal
The metabolic responses to injury and critical illness occur simul- circulation. More important, perhaps, the gut can be a portal of en-
taneously.They primarily involve the liver, skeletal muscle, the gut, try for bacteria and bacterial toxins, which can worsen or perpetuate
the kidneys, and the wound or focus of inflammation [see Figure 3]. critical illness [see 8:13 Multiple Organ Dysfunction Syndrome].
The heart also plays a major role by providing the motive force for The kidneys also contribute to the generalized increase in physio-
the high rate of blood flow that is required to support increased ex- logic work and energy requirements that accompanies critical illness.
change of nutrients and other substances between organs.The cen- The kidneys must excrete an increased solute load consisting of urea,
tral and autonomic nervous systems and endocrine tissues are main- potassium, magnesium, weak acids, and other intracellular constitu-
ly involved in regulation of the responses. ents. In addition, many drugs and their metabolites depend on renal
The wound, which may include one or more foci of infection and excretion. Production of ammonia from glutamine may be increased
other sites of inflammation in addition to external injuries, plays a to neutralize acid loads. Many of these processes require energy.
principal role. It acts as a large arteriovenous shunt, robbing the host All of these regional metabolic processes occur simultaneously.The
of blood supply and demanding increased cardiovascular work.The net integrated metabolic response is evident clinically as increased en-
wound also induces and controls profound metabolic changes, which ergy expenditure and heat production, fever, accelerated nitrogen ex-
subside as the wound heals.Tissues are broken down, presumably to cretion and muscle wasting, and glucose intolerance.The wound ap-
provide substrates for a variety of synthetic and energy-producing pears to exert a controlling influence on the intensity and duration of
processes.The cost to the patient is increased metabolic work, elevat- the responses to critical illness or injury: the intensity is proportional to
ed energy requirements, erosion of lean body tissue, and debility. the size of the wound or the mass of inflammatory tissue.The larger
The healing wound is a site of intense metabolic activity. Dissolu- the wound, the more intense the metabolic responses. As the wound
tion and removal of necrotic tissue, containment and killing of bacte- heals and as inflammation subsides, the heightened metabolic de-
ria, collagen synthesis and wound repair, cellular proliferation, and mands abate. Expeditious wound closure and definitive treatment of
restoration of tissue integrity occur, often simultaneously. These pro- infection are the most effective forms of anticatabolic therapy.
cesses require energy and a variety of substrates, particularly amino
acids for protein synthesis.The microenvironment of a wound is often
relatively hypoxic. However, inflammatory cells have a marked capaci- Hypermetabolism
ty for glycolytic metabolism,15 in which adenosine triphosphate (ATP) Because humans maintain fairly constant body temperature, the
can be generated without the consumption of oxygen.This capacity heat generated by the body is equal to the heat lost in biochemical
persists even when oxygen delivery is sufficient. Glucose is thus the and physiologic processes and is an indicator of overall metabolic ac-
principal fuel for the healing wound. It is metabolized to lactate, which tivity.This heat ultimately results from the oxidation of organic fuels.
is then released into the circulation for transport to the liver. The rate of heat production, or metabolic rate (MR), is therefore re-
The liver produces the additional glucose that is required by the ˙ ˙
lated to VO2 and VCO2. It may be measured directly by means of di-
wound. It is capable of manufacturing glucose from lactate. In this rect calorimetry, or it may be calculated from measurements of VO2,˙
manner, glucose is recycled between the liver and the wound, and ˙
VCO2, and body surface area (BSA) by means of indirect calorimetry:
there is no net gain or loss of carbon atoms.The liver also synthesizes
glucose from amino acids, principally alanine, which comes from MR (kcal/m2/hr) =
both skeletal muscle and the gut.This mechanism is termed gluco- ˙ ˙
[(3.9 × VO2 [L/min]) + (1.1 × VCO2 [L/min])] × 60 (min/hr)
neogenesis.The nitrogen contained in the amino acids is converted BSA (m2)
to urea and excreted.The liver also synthesizes a variety of circulating
proteins in response to inflammation and infection (so-called acute- A third term, –3.3 × urea nitrogen loss (g/time), is sometimes added
phase proteins). All of these synthetic processes require energy, pro- to account for the heat produced by urea formation. However, it is
duced in part by fat oxidation, and therefore contribute to a general usually a small factor, adjusting MR by only 2% to 3%.16
increase in energy utilization, heat production, and metabolic rate. Values determined by direct and indirect calorimetry under steady-
Skeletal muscle protein breaks down at an accelerated rate after state conditions are comparable.17 When metabolic rates of normal
injury and critical illness, releasing a variety of substances into the individuals are determined under controlled basal conditions, the
circulation, including creatine and creatinine, 3-methylhistidine, po- values are reproducible and predictable (± 12%) on the basis of age,
tassium, magnesium, and amino acids.The amino acids serve as pre- sex, and body size.18 When metabolic rates of critically ill patients
cursors for protein synthesis in the wound and in the liver. The with satisfactory hemodynamic function are determined under sim-
released amino acids do not reflect a simple dissolution of protein. ilar conditions, the rates are greater than predicted. Thus, patients
Rather, alanine and glutamine are disproportionately released. Ala- are said to be hypermetabolic.
nine can be readily converted to glucose in the liver. Glutamine serves The degree of hypermetabolism is proportional to the severity of ill-
both as a fuel—especially for the gut and for rapidly proliferating ness.This phenomenon was most dramatically demonstrated in careful
cells, including inflammatory cells and fibroblasts—and as a precur- studies of burn patients performed in the 1970s.19 The increase in rest-
sor for renal ammonia production, which is an important mecha- ing metabolic rate was proportional to the extent of tissue injury—that
nism for neutralizing excreted acid loads. is, to the amount of the BSA that was burned. Hypermetabolism has
Although muscle tissue in healthy persons is usually quite sensi- also been demonstrated in a variety of other critically ill patients, but it
tive to insulin and commonly serves as a site of glucose storage, mus- has usually been less severe than that seen in patients with major burns.20

10. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 10
WOUND
Lactate ATP
Heat
LIVER
Glucose
Lactate
Amino Acids/
Urea Glutamine
Glucose
Amino Acids
Alanine Glucose
Acute-Phase
Ammonia
Proteins Pyruvate
Free
Alanine
Amino Acids
Glutamine
Alanine MUSCLE
Ammonia
Glutamine
GUT
Glutamine
Glutamine
Urea
Ammonia
NITROGEN
LOSS KIDNEY
Urea
Amnonia
Figure 3 The metabolic response to critical illness includes characteristic alterations in the ex-
change of substrates between organs. Presumably, these responses occur in support of the heal-
ing wound and are facilitated by a hyperdynamic circulation.The wound requires glucose (and
probably glutamine) as a primary respiratory fuel. Glucose is converted to lactate; this conver-
sion can occur in an aerobic environment. Lactate is transported to the liver for conversion back
into glucose.The recycling of lactate to glucose is a major pathway that requires the input of en-
ergy and thereby contributes to increased energy utilization. Most of the glucose required for the
healing wound (i.e., inflammatory tissue) is produced by the liver, not only from lactate but also
from alanine and other glucogenic amino acids.These reactions require energy and also result in
the formation of urea. Muscle is the major source of amino acids, which are used for protein
synthesis both in the wound and in the liver.The most abundant amino acids released from mus-
cle are alanine and glutamine. Glutamine serves as a primary fuel for the gut, producing ammo-
nia and other products (e.g., alanine) that are processed by the liver. In addition, glutamine may
help buffer filtered acid loads in the kidneys by the formation of ammonia.These metabolic
processes contribute to the hypermetabolism, hyperdynamic circulation, increased nitrogen
loss, and glucose intolerance that are clinically evident in critically ill patients.
In the burn patients, moreover, there was a limit to the hypermetabo- with very large burns were exposed to cold temperatures, their al-
lism: metabolic rates of patients with extensive burns were little differ- ready high metabolic rates did not increase but actually fell.19 None
ent from those of patients with burns covering 50% to 60% of BSA. of these patients survived the injury, presumably because of inability
These observations suggest that there is a limit to the metabolic to respond to new stresses. In another group of burn patients, the in-
activity that patients can support in response to critical illness.The ability to increase metabolic rate to facilitate rewarming after skin
difference between this limit and the magnitude of the patient’s actu- grafting procedures also identified nonsurvivors.21 When patients are
al responses defines physiologic reserve [see Figure 4]. Physiologic re- cared for in a warm environment, hypermetabolism is reduced and
serve is presumably also affected by the patient’s age and state of physiologic reserve is increased.
health before the critical illness. It reflects the patient’s ability to meet Hypermetabolism refers to an increase in total body oxidative me-
additional complicating stresses, such as infection, volume loss, pain, ˙
tabolism that is manifested by increases in total body VO2, cardiac
anxiety, and cold ambient temperatures. For example, when patients ˙
output, and MR. Regional VO2 is generally increased throughout
are exposed to progressively colder ambient temperatures, the meta- most tissue beds, but regional blood flow is not.The additional total
bolic rate generally increases. However, when a group of patients body flow is directed largely to the wound or site of inflammation

11. © 2004 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 11
and to the splanchnic circulation, and it appears to supply the Limit of Metabolic Response
wound with increased amounts of glucose and other nutrients. In
studies of patients who had sustained a large burn on one leg and no
˙
burn on the other,Wilmore and colleagues found that VO2 of both Physiologic
limbs was increased in proportion to the total BSA burned and rep- Reserve
˙
resented a fairly constant 6% of total body VO2.22 However, blood
flow to the injured extremity was approximately twice that to the un-
Metabolic Response
injured limb. Blood flow was proportional to the extent of the local
injury and was directed to the surface wound.23
Oxygen consumption by the splanchnic and renal circulations Response to
˙
also increases in proportion to total body VO2 and hence in propor- Critical Illness
tion to total body injury.24 Splanchnic flow increases in proportion to
total body flow (cardiac output), and together with the blood flow to
the wound, it accounts for a large part of the increase in cardiac out-
put in critically ill patients.25 The increase in renal blood flow corre-
˙
lates with solute load rather than with VO2. From these and other
studies, it is possible to calculate how oxygen consumption and car-
diac output are partitioned among different vascular beds.26 Severity of Critical Illness
Figure 4 The intensity of the metabolic response to critical surgical
illness increases as a function of the severity of illness. In patients with
Altered Temperature Regulation
extremely severe critical illness (e.g., patients with burns covering 60%
Body temperature is determined by the balance between heat pro- of the body surface area), responses are near maximal, and physiologic
duction and heat loss. It is normally closely regulated and maintained reserves, with which patients respond to additional stressors (e.g., in-
within a narrow range. Critically ill patients typically have an elevated fection, hemorrhage, or cold exposure), are limited. Patients may also
body temperature, even in the absence of clinical infection.27 Heat have limited physiologic reserves because of preexisting disease, star-
production, as measured by metabolic rate, is increased in the criti- vation, or advanced age.Therapies that attenuate the stressors of criti-
cal surgical illness improve physiologic reserve.
cally ill patient. Heat loss may also be elevated in these patients.
It was once thought that increased evaporative heat loss was the
driving force for hypermetabolism, at least in burn patients.28,29 Barr bertson first described this phenomenon in patients with long-bone
and associates tested this assumption.30 Although patients treated in fractures.27 Similar observations were made by Howard and associ-
warm, dry air showed substantially increased evaporation of water ates in the United States.33 Cuthbertson concluded that injured and
from the burn wound and more rapid drying of the wound surfaces uninjured skeletal muscle was the source of the excreted nitrogen.34,35
than did patients exposed to normal ward conditions, they had re- As skeletal muscle protein is degraded, a variety of markers are re-
duced hypermetabolism and a smaller degree of weight loss. leased into the circulation and then excreted by the kidneys. In-
Several other studies have examined the relation between thermo- creased excretion of several of these markers36,37 has been observed
regulatory factors (evaporative heat loss and ambient temperature) in patients with trauma,36,38 burns,39 and infections.40
and hypermetabolism. For example, the metabolic rates of burn pa- There are other sources of nitrogen loss in critically ill patients, in-
tients were determined at several ambient temperatures, ranging cluding loss of tissue from slough or excision, loss of blood and exu-
from 19° to 33° C (66.2° to 91.4° F) [see Table 3].31 Metabolic rate date, and loss of mucosa from the GI tract. Cuthbertson estimated
decreased as ambient temperature was increased, but core tempera- that in the first 10 days after a burn, the amounts of nitrogen lost as a
ture remained elevated at all ambient temperatures, indicating that result of direct tissue injury, wound exudation, generalized catabo-
thermoregulation in these patients occurred in relation to an elevat- lism, and atrophy were roughly equivalent.41 Moore and coworkers
ed central reference temperature.When febrile burn patients in an- measured nitrogen loss in the wound exudate of burn patients.This
other study were allowed to set the ambient temperature to achieve wound loss accounted for as much as 20% to 30% of total nitrogen
thermal comfort, they invariably preferred higher than normal tem- loss during the early postburn period.42
peratures, in the range of 30° to 33° C (86.0° to 91.4° F).32 The pa- The time course of nitrogen excretion during critical illness is
tients’ unburned skin remained relatively vasoconstricted at the high-
er temperatures as an additional way of maintaining the febrile state. Table 3—Effect of Ambient Temperature on
However, even under these conditions of thermal comfort, the pa-
tients continued to maintain elevated metabolic rates.Thus, although
Metabolic Rate and on Core and Skin Temperatures
thermoregulatory factors may influence hypermetabolism, the in-
Ambient Core Skin Metabolic
creased rate of heat production appears to be determined primarily Temperature N Temperature Temperature Rate
by metabolic factors. Hypermetabolism is temperature sensitive but (°C) (°C) (°C) (kcal/m2/hr)
not temperature dependent.
Normal subjects
21 3 36.7 30.0 41.2
Altered Protein Metabolism 25 4 36.8 31.4 35.6
33 4 36.8 34.2 36.3
MUSCLE WASTING, NITROGEN LOSS, AND ACCELERATED
Burn patients
PROTEIN BREAKDOWN (45% TBS)
One of the most striking features of the metabolic response to criti- 21 9 38.1 32.1 83.7
25 20 38.5 33.1 63.5
cal illness is the marked degree of muscle wasting.This atrophy is as-
33 20 38.0 36.2 62.0
sociated with increased urinary excretion of nitrogen. Sir David Cuth-

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8 CRITICAL CARE 25 Metabolic Response To Critical Illness — 12
distinctive. Cuthbertson observed that nitrogen excretion peaked Table 4—Alterations in Rates of Protein
several days after injury and gradually returned to normal during a Synthesis and Catabolism That May Affect
period of several weeks.34 The pattern was similar to that of in- Hospitalized Patients
creased oxygen consumption. Thus, both hypermetabolism and
muscle proteolysis peak shortly after the onset of critical illness and Synthesis Catabolism
gradually return to normal as recovery proceeds.This too appears
to be a characteristic feature of the metabolic responses to critical Normal—starvation ↓ 0
illness [see Figure 2].43-45 Normal—fed, bed rest ↓ 0
Protein turnover is an indicator of overall protein metabolic activ- Elective surgical procedure ↓ 0
ity. It is determined through use of tracers. Both extracellular and in- Injury/sepsis—I.V. dextrose ↑↑ ↑↑↑
tracellular amino acids are considered part of a free amino acid pool. Injury/sepsis—fed ↑↑↑ ↑↑↑
Nitrogen is added to this pool by nitrogen intake (diet) and by pro- ↓—decrease—↑—increase—0—no change
tein breakdown. Nitrogen is removed by protein synthesis and by
conversion to urea.When a small quantity of a labeled amino acid is acids.57 The net release of amino acid nitrogen was five times greater
infused, the rate of appearance of nitrogen in the free amino acid in burn patients than in control subjects. Alanine was the only amino
pool can be determined. Under steady-state conditions, this appear- acid whose release rate was significantly elevated (glutamine concen-
ance rate represents protein turnover and matches protein disap- tration was not determined).Alanine release was related to total burn
pearance.46 During critical illness, protein turnover is increased.47 ˙
size (injury severity) and to total body VO2. In related studies, the ac-
When nitrogen turnover data are combined with measurements of celerated peripheral amino acid release was matched by increased
nitrogen intake and loss, rates of total body protein synthesis and ca- uptake across the splanchnic bed.24 Alanine uptake was three to four
tabolism can be estimated.These estimates indicate that protein ca- times control values.This increased release of amino acids from the
tabolism is increased in critically ill patients.48 Synthesis rates remain periphery and transport to splanchnic tissues appears to be another
normal during fasting but increase to approach or match catabolic characteristic metabolic response to critical burn injury.
rates when feeding is adequate. Thus, the increase in net nitrogen Garber and colleagues observed that glutamine and alanine to-
loss during critical illness appears to result from an increase in pro- gether constituted as much as 70% of the amino acids released from
tein breakdown. Decreased protein synthesis is less of a factor as skeletal muscle in vitro.58 Furthermore, the release rates of alanine
long as nutritional intake is satisfactory [see Table 4]. and glutamine reflected the net rates of formation from other amino
acids.59 Thus, during critical illness, skeletal muscle protein is broken
ALTERED AMINO ACID METABOLISM
down into amino acids that are largely converted to glutamine and
Protein synthesis and breakdown are processes that occur in cells alanine, which are then released into the ECF for transport. Al-
and involve intracellular amino acids. It has been estimated that skel- though all amino acids are required for protein synthesis at remote
etal muscle contains as much as 80% of the free amino acid pool.49 locations, glutamine and alanine are the major nitrogen carriers from
Intracellular concentrations of free amino acids in skeletal muscle are muscle.These two amino acids have other roles as well. Alanine is a
approximately 30 times greater than plasma concentrations of free precursor of glucose production in the liver. In that process, urea is
amino acids.50 Thus, the total muscle mass of a 70 kg man contains also formed and subsequently excreted by the kidneys. Although
approximately 87 g of free amino acids in the intracellular water, there may be some minor recycling of urea nitrogen under certain
whereas the extracellular pool contains only 1.2 g. conditions,60 formation of urea is the final step in the loss of body
The relative amounts of individual free amino acids in cells differ protein, representing an irreversible loss of nitrogen.
from the proportions found in protein.Glutamine,a nonessential amino Glutamine is a precursor for production of ammonia in the kid-
acid, accounts for only about 5% to 6% of protein, but it is the most neys, an important buffering mechanism for excreted acid loads. In-
abundant intracellular free amino acid, accounting for about 60% of creased breakdown of intracellular constituents could result in such
the total intracellular free amino acid pool. In contrast, the eight es- an acid load, and ammonia excretion is often increased after injury.
sential amino acids together account for only 8.4% of the intracellu- Intracellular skeletal muscle glutamine may be an important deter-
lar pool.The intracellular concentration of glutamine decreases un- minant of net skeletal muscle protein breakdown.61,62 After a stan-
der many catabolic conditions, including starvation, inactivity,51 elective dard operation in an animal model, net amino acid efflux from the
operation,52 trauma,53 and sepsis.54 This decrease occurs early in the hindquarter was increased as the glutamine concentration fell. How-
course of the acute illness, persists until late in convalescence, and ever, if the intracellular glutamine concentration was maintained by
appears to be related to the severity of illness.55,56 The intracellular the provision of exogenous glutamine, net efflux was reduced.
concentrations of phenylalanine, tyrosine, alanine, and the branched- Glutamine also appears to be an important respiratory fuel for
chain amino acids (BCAAs)—leucine, isoleucine, and valine—typically rapidly dividing cells. Glutamine can be converted to glutamate and
increase after trauma and infection.51,54 These levels return to normal then to α-ketoglutarate for participation in the citric acid cycle.The
during convalescence, usually before glutamine levels do. nitrogen of glutamine is used to form ammonia, alanine, and citrul-
Plasma concentrations of free amino acids generally decrease after line.63 This process occurs in colonocytes, enterocytes, fibroblasts,
operation, injury, or infection, largely because of a fall in the concen- and, possibly, inflammatory cells such as macrophages. Phagocytic
trations of the nonessential amino acids. Changes in extracellular cells are found in fixed locations in the GI tract, such as Peyer’s
concentrations of specific amino acids have been inconsistent be- patches and other regions containing Kupffer’s cells, as well as in the
tween studies, presumably as a reflection of differences in patient se- wound, at other sites of inflammation, and in the bone marrow.
lection, analytic methods, or treatment.54 Windmueller measured the nutrient requirements of the rat intestine
The ECF compartment is important for amino acid transport be- using an isolated, perfused segment of small bowel.63 The intestinal
tween organs and between regions of the body. Aulick and Wilmore segment extracted large amounts of glutamine from the recirculated
calculated amino acid release rates from peripheral tissues of burn perfusate. Souba and Wilmore measured amino acid uptake by the
patients on the basis of measurements of leg blood flow and of gut in conscious animals and demonstrated that the consumption of
femoral arterial and venous plasma concentrations of 10 amino glutamine by the gut was significantly increased after celiotomy, even